PHYCO’DERM® Takes care of the delicate area around the eyes * Multiple ways of action Stimulates the major defense systems for increasing resistance against environmental stressors Improves the dermis properties for smoothing fine lines and wrinkles of crow’s feet Minimizes the appearance of under-eye dark circles for erasing the look of fatigue Reduces the volume of under-eye bags for alleviating skin puffiness “The eyes are the mirror of the soul and reflect everything that seems to be hidden and like a mirror they also reflect the person looking into them” - Paulo Coelho. The skin around the eyes is perceived as an essential feature of facial beauty since it immediately reflects fatigue. It also appears as the first visible area to exhibit the changes of ageing that include dark under-eye circles, “bagging” or loss of elasticity, “crow’s feet” or wrinkling and loss of opacity of the under-eye skin. It can too reflects one’s lifestyle to a certain extent e.g . stress, use of tobacco and exposition to ultraviolet radiations. In fact, the skin of the periocular area is distinct from other parts of the facial skin. Why? - This area is extremely thinner than anywhere else on the face and under constant moving. So it is rapidly affected by the signs of time. Smiling, squinting and blinking promote wrinkles from the repetitive contraction of the underlying muscle, leading to the development of crow’s feet. Moreover when we age, the firmness and elasticity of the skin of eyelids decrease. - This area lacks the natural moisture because the fewer presence of sebaceous glands. So it often appears dehydrated. The stratum corneum on eyelids presents a high trans-epidermal water loss (TEWL). With ageing, it exists a trend towards lower skin dehydration making the skin barrier in the periocular area more vulnerable. - This area is more sensitive to injuries than the rest of the skin face due to constant exposure of environmental stressors ( e.g . UV, smoke, fumes, wind..) that can be exacerbated by stress, lack of sleep, poor diet and allergies . - This area can often show fragility of the fine and dense capillary network and a deficiency of the lymphatic system that lead to dark-circles and puffiness under the eyes which are considered to be unattractive. Thus the skin around the eyes mandates earlier and more aggressive protection to avoid early ageing damage and combat the look of fatigue. Several facial rejuvenation procedures help reverse the signs of facial ageing by the cosmetic, pharmaceutical, medical and plastic surgery industries. However many such methods and devices involve substances that are toxic ( e.g . botulinum toxin), require injection (e.g . hyaluronic acid) or surgical procedures ( e.g . blepharoplasty). Many of them are costly, less effective and not suitable for long-term use due to undesirable side effects. Therefore it occurs a growing demand for non-invasive, effective and risk-free cosmetic agent which can reduce and or minimize the appearance of defects of the region around the eyes in order to provide a short and long-term youthful and revitalized look. GELYMA proposes PHYCO’DERM® that offers a natural multi-target science based approach for taking care of the delicate area around the eyes by improving the aesthetic appearance with major benefits (e. g . protection against harmful environmental aggressors, enhancement of firmness and elasticity, attenuation of fine lines and wrinkles of crow’s feet, reduction of puffiness and dark circles under the eyes). As results the periocular area appears refreshed and less fatigued. PHYCO’DERM® combines, in a glycerin excipient, two potent seaweed extracts prepared from the brown seaweed Undaria pinnatifida and the red one Corallina officinalis, chosen because of their particular biochemical benefits. Glycerin helps replenish moisture in the stratum corneum for keeping the skin hydrated and supple. 2 Mechanisms of action The mechanisms of action of PHYCO’DERM has been demonstrated by using the transcriptomic analysis on normal human fibroblasts for the gene expression analysis using the DNA chip technology from AFFYMETRIX (collaboration Strati CELL-Belgium) completed by other in vitro testing (collaboration SEPHRA PHARMA-France) and clinical studies (collaboration FARCODERM-Italy) in order to provide valuable data. PHYCO’DERM stimulates major defense systems for increasing resistance against environmental stressors Because of its extreme thinness, the skin around the eyes is particularly sensitive to adverse impact of external factors (e.g. bacterial infection, oxidative stress, UV and various environmental pollutants) that may cause irritation and itching sensation. Protection against microbial infections & associated inflammation The periorbital region may be affected by inflammation due to various infections, especially infections of the dermis and associated tissues around the eyes. Swelling of eyelids is a common symptom of inflammation and allergy . Chemokines are a class of cytokines acting as secondary inflammatory mediators induced by numerous cells (e.g. Gene Expression P value Gene name keratinocytes and fibroblasts) after different signals, specially abbreviation change* (t-test) bacterial infections. It exists two families of chemokines: CC and CCL2 3.13 2.40E -06 CC chemokines CXC chemokines. CCL11 2.34 3.80E -02 CXCL1 2.62 2.60E -05 CXC chemokines PHYCO’DERM® is capable to overexpress the gene CXCL2 1.23 6.60E -04 expression of both chemokines families highly involved in *relative expression compared to untreated control inflammatory response. Toll-like receptors (TLRs) represent a family of pattern recognition receptors known for their role in inflammation and Gene Expression P value Gene name innate immunity. abbreviation change* (t-test) Toll -like receptor 6 TLR6 1.79 7.90E -04 PHYCO’DERM® is capable to overexpress the gene Toll -like receptor 3 TLR3 1.38 3.40E -02 expression of two TLRs. *relative expression compared to untreated control Their complementary action with chemokines helps enhance /or restore natural adaptive immune responses in the skin. The genes TNFAIP3 and NFKBIA play a key role in the negative Gene Expression P value Gene name regulation of Nf-kappa B signalling in response to multiple abbreviation change* (t-test) stimuli. The gene BIRC3 is an important inhibitor of apoptosis. Tumor necrosis factor TNFAIP3 1.31 3.80E -02 Nuclear factor of PHYCO’DERM® is able to influence major negative kappa light NFKBIA 1.32 1.80E-02 regulators of inflammatory process. Therefore it reduces polypeptide gene inflammation that can also lead to vessel fragility in the Apoptosis inhibitor 2 BIRC3 1.42 1.70E -02 periocular area. *relative expression compared to untreated control PHYCO’DERM® would be able to: 1- enhance immune adaptive response against microbial aggressions by combining the chemotactic activity of CC and CXC chemokines with the recognition of microbial components linked to toll-like receptors (TLRs), 2- regulate the inflammatory response related to the transcription NF-kappa B signalling known as a crucial player in inflammation and immunity processes. Therefore, PHYCO’DERM® may also help neutralize irritation and reinforce the barrier function of the skin by eliminating bacterial infections and fighting against possible allergic and inflammatory diseases that may occur on the eyelids. 3 Protection against oxidative stress & regulation of cellular redox state The periorbital region may be highly affected by constant exposure of environmental factors e.g. UV radiations, exhaust fumes, cigarette smoke that cause tissue damage and ageing. Skin cells respond to these harmful stressors through a wide range of interlinked defense mechanisms. Oxidative stress activates numerous major signalling pathways resulting in changes in gene expression which influence the ability of cells to survive. One of the most important regulators is the Nrf 2 factor. Gene Expression P value Gene names abbreviation changes (t-test) Genes that are regulated by Nrf2 encode proteins that include: NAD(P)H dehydrogenase NQO1 1.59 1.90E-04 several enzymes e.g. NQO1, GCLM quinone1 Glutamate -cysteine GCLM 2.21 2.80E-05 other antioxidant proteins e.g. HSP Proteins (specially ligase HSP70 known to enhance cell survival, prevent apoptosis & Solute carrier family 7 SLC7A11 1.83 4.90E -05 reduce oxidative stress) and thioredoxins, glutaredoxins Glucose -6-phosphate G6PD 1.33 1.90E-03 sulfiredoxins systems known to have pivotal role in redox dehydrogenase signalling for controlling cell metabolism. Heat shock 70kDa HSPA2 1.37 6.70-03 protein 2 Thioredoxin reductase 1 TXNRD1 1.36 1.90E -03 PHYCO’DERM® is able to influence the Nrf 2 factor via the activation of several pathways in order to: Sulfireredoxin 1 SRXN1 1.47 2.90E -03 Glutaredoxin GLRX 1.23 1.10E -02 - increase the cytoprotection against oxidative stress *relative expression compared to untreated control - regulate the cellular redox state from the detrimental effects of reactive oxygen species by acting through several signalling & transcriptional processes in cells. Reinforcement of detoxification systems Major air pollutants affects the skin, especially the periocular area. Depending of the nature of these pollutants and skin integrity, their modes of penetration differ but their effects contribute to skin ageing, atopic dermatitis and skin cancer. These environmental factors stimulate skin response through a wide range of interlinked defense mechanisms. Metallothioneins (MT) are ubiquitous proteins